Endogenous, non telomeric Reverse Transcriptase (RT) is an enzyme encoded by two classes of abundant repeated elements in all eukaryotic genomes: retrotransposons and endogenous retroviruses (di Marzo Veronese F, Copeland T D, DeVico A L, Rahman R. Oroszlari S, Gallo R C, Samgadharan M G Science (1986) 231, 1289-91—Characterization of highly immunogenic p66/p51 as the reverse transcriptase of HTLV-III/LAV; Grob P M, Wu J C, Cohen K A, Ingraham R H, Shih C K, Hargrave K D, McTague T L, Merluzzi V J AIDS Res Hum Retroviruses (1992) 8, 145-52 Nonnucleoside inhibitors of HIV-1 reverse transcriptase: nevirapine as a prototype drug). Expression of RT-coding genes is generally repressed in terminally differentiated non pathological, tissues—where it is detectable only at a basal levels—yet is highly active in the mammalian germline, embryonic tissues and tumor cells. The role played by RT in such fundamental processes as cell growth and differentiation remains to be clarified.
Nevirapine, Efavirenz and Rescriptor, also known under the commercial names of VIRAMUNE®, SUSTIVA® and RESCRIPTOR® respectively, are known as non-nucleosidic inihibitors of RT and are widely used in the therapy of AIDS as antiretroviral agents. In particular nevirapine has the following empirical formula C15H14N4O. In its pure state it is a crystalline solid of molecular weight 266.302, with a melting point of 247-249° C. and solubility of 0.1 mg/ml in water and 5.5 mg/ml in ethanol and can be prepared according to the indications present in patent EP 429.987. Nevirapine (5,11-dihydro-11-cyclopropyl-4-methyl-6H-dipyrido-[3,2-b:2′,3′-e][1,4]diazepin-6-one) is comprised in the group of compounds of the 5,11-dihydro-6H-dipyrido[3,2-b:2′,3′-e][1,4]diazepines, which are known as non-nucleosidic inihibitors of RT and used in the prevention and treatment of HIV infections, as described in EP 429.987.
Efavirenz (M.W. 315.68) (−)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4,-dihydro-2H-3,1-benzoxazine-one [References herein incorporated by reference: 1.YOUNG, S. D.; BRITCHER, S. F.; TRAN, L. O.; PAYNE, L. S.; LUMMA, W. C.; LYLE, T. A.; HUFF, J. R.; ANDERSON, P. S.; OLSEN, D. B.; CARROLL, S. S.; PETTIBONE, D. J.; O'BRIEN, J. A.; BALL, R. G.; BALANI, S. K.; LIN, J. H.; LONG, W. J.; BYRNES, V. W.;EMINI, E A.; ET AL., L-743,726(DMP-266): A NOVEL, HIGHLY POTENT NONNUCLEOSIDE INHIBITOR OF THE HUMAN IMMUNODEFICIENCY VIRUS TYPE 1 REVERSE TRANSCRIPTASE. ANTIMICROB AGENTS CHEMOTHER 39(12):2602-2605 (1995)]
Rescriptor (M.W. 552.68) [1-(5-methanesulphonamido)-1H-indol-2-yl-carbonyl)-4-[3-(isopropylamino)-2-pyridinyl]piperazine] (References herein incorporated by reference: 1. ROMERO, D. L.; MORGE, R. A.; GENIN, M. J.; BILES, C.; BUSSO, M.; RESNICK, L.; ALTHAUS, I. W.; REUSSER, F.; THOMAS, R. C.; TARPLEY, W. G. BIS(HETEROARYL)PIPERZINE(BHAP) RT INHIBITORS: STRUCTURE-ACTIVITY RELATIONSHIPS OF NOVEL SUBSTITUTED INDOLE ANALOGUES AND THE IDENTIFICATION OF MONOMETHANESULFONATE(U-90152S). J MED CHEM 36(10):1505-1508 (1993).
2. ROMERO, D. L.; OLMSTED, R. A.; POEL, T. J.; MORGE, R. A.; BILES, C.; KEISER, B. J.; KOPTA, L. A.; FRIIS, J. M.; HOSLEY, J. D.; STEFANSKI, K. J.; WISHKA, D. G.; EVANS, D. B.; MORRIS, J.; STEHLE, R. G.; SHARMA, S. K.; YAGI, Y.; VOORM AN, R. L.; ADAMS, W. J.; TARPLEY, W. G. TARGETING DELAVIRDINE/ATEVIRDINE RESISTANT HIV-1: IDENTIFICATION OF (ALKYLAMINO)PIPERIDINE-CONTAINING BIS(HETEROARYL)PIPERAZINES AS BROAD SPECTRUM HIV-1 REVERSE TRANSCRIPTASE INHIBITORS. J MED CHEM 39(19):3769-3789 (1996).
Preliminary studies in our group have shown that both nevirapine and efavirenz cause an early and effective developmental arrest in early mouse embryos when added to cultures of embryos prepared in in vitro fertilization (IVF) assays. That observation first indicated that both drugs can potentiality inhibit cell proliferation and prompted us to test their effect on tumor cells.